A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor

Monika Szabo, Tracey Huynh, Celine Valant, J Robert Lane, Patrick M Sexton, Arthur Christopoulos, Ben Capuano

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Positive allosteric modulators (PAMs) targeting the M4 muscarinic acetylcholine receptor (mAChR) offer greater sub-type selectivity and unique potential as central nervous system agents through their novel mode of action to traditional orthosteric ligands. In an attempt to elucidate the molecular determinants of allostery mediated by the exemplar thienopyridine M4 mAChR PAM, LY2033298, we report herein a systematic structure-activity relationship (SAR) study investigating different linkage points, halogen replacements to examine size and electronic effects, and different substitution combinations on the thienopyridine scaffold. We applied an operational model of allosterism to determine values of functional affinity (KB), cooperativity (αβ) and intrinsic agonism (τB) for all compounds.
Original languageEnglish
Pages (from-to)1998-2003
Number of pages6
JournalMedChemComm
Volume6
Issue number11
DOIs
Publication statusPublished - 2015

Cite this

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title = "A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor",
abstract = "Positive allosteric modulators (PAMs) targeting the M4 muscarinic acetylcholine receptor (mAChR) offer greater sub-type selectivity and unique potential as central nervous system agents through their novel mode of action to traditional orthosteric ligands. In an attempt to elucidate the molecular determinants of allostery mediated by the exemplar thienopyridine M4 mAChR PAM, LY2033298, we report herein a systematic structure-activity relationship (SAR) study investigating different linkage points, halogen replacements to examine size and electronic effects, and different substitution combinations on the thienopyridine scaffold. We applied an operational model of allosterism to determine values of functional affinity (KB), cooperativity (αβ) and intrinsic agonism (τB) for all compounds.",
author = "Monika Szabo and Tracey Huynh and Celine Valant and Lane, {J Robert} and Sexton, {Patrick M} and Arthur Christopoulos and Ben Capuano",
year = "2015",
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language = "English",
volume = "6",
pages = "1998--2003",
journal = "MedChemComm",
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publisher = "The Royal Society of Chemistry",
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A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor. / Szabo, Monika; Huynh, Tracey; Valant, Celine; Lane, J Robert; Sexton, Patrick M; Christopoulos, Arthur; Capuano, Ben.

In: MedChemComm, Vol. 6, No. 11, 2015, p. 1998-2003.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor

AU - Szabo, Monika

AU - Huynh, Tracey

AU - Valant, Celine

AU - Lane, J Robert

AU - Sexton, Patrick M

AU - Christopoulos, Arthur

AU - Capuano, Ben

PY - 2015

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AB - Positive allosteric modulators (PAMs) targeting the M4 muscarinic acetylcholine receptor (mAChR) offer greater sub-type selectivity and unique potential as central nervous system agents through their novel mode of action to traditional orthosteric ligands. In an attempt to elucidate the molecular determinants of allostery mediated by the exemplar thienopyridine M4 mAChR PAM, LY2033298, we report herein a systematic structure-activity relationship (SAR) study investigating different linkage points, halogen replacements to examine size and electronic effects, and different substitution combinations on the thienopyridine scaffold. We applied an operational model of allosterism to determine values of functional affinity (KB), cooperativity (αβ) and intrinsic agonism (τB) for all compounds.

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U2 - 10.1039/c5md00334b

DO - 10.1039/c5md00334b

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JF - MedChemComm

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